Abstract HIV infected adults who drink alcohol are already physiologically frail due to HIV infection, comorbidity (including hepatitis C infection), polypharmacy and associated substance use. In this setting, biomedical consequences of alcohol use can occur at lower risk use and may be unappreciated or misattributed. The ?Consortium to improve OutcoMes in HIV/Aids, Alcohol, Aging & multi-Substance? (COMpAAAS) is supported by NIH/NIAAA award U24AA020794 to study this issue in a single sample, the Veterans Aging Cohort Study (VACS). In this set of three applications, the Antiretroviral Therapy Cohort Collaboration (ART-CC) and Kaiser Permanente (KP) teams join the Veterans Healthcare System (VA) team as COMpAAAS Tripartite: ART-CC, KP, and VA. Our long term goal is to inform intervention design and implementation. Together we will study biomedical consequences of alcohol and associated substance use in HIV extending the scope and generalizability of VACS from a single national healthcare system to 12 systems across 10 North American and European countries, doubling the HIV+ sample and substantially increasing the diversity of subjects. Importantly, COMpAAAS Tripartite also extends the pool of uninfected comparators (more women, young patients, and HCV+) available for analyses, a critical step if we are to understand how alcohol differentially affects individual biomedical outcomes by HIV status by gender, age, and HCV status. Using propensity and related methods and variables tailored to each aim and hypothesis, we will closely match HIV+ subjects with uninfected comparators drawing from 3.7 million KP members (1.9 million women) and 5 million veterans born in 1945-1965 (Birth Cohort, includes 450,000 HCV+). ART-CC, KP, and VA will also participate in an HIV+ substudy (n=2250), The Medications, Alcohol, Substance use in HIV Study (MASH), involving new, prospective data on potentially inappropriate medications (PIMS) and direct biomarker measurements for alcohol and associated substances (tobacco, marijuana, opioids, cocaine, and methamphetamine). ART-CC, KP and VA have identical aims and protocols and contribute and share data. Aims compare HIV infected and uninfected individuals and address: 1) attributable risk from alcohol and tobacco for all cause and cause specific hospitalization and mortality; 2) the impact of alcohol and tobacco on primary and secondary preventative care; and 3) the role of alcohol and ART on drug interactions (potentially inappropriate medications) leading to adverse biomedical consequences. VA will coordinate sharing limited data sets based on the HIV Cohorts Data Exchange Protocol (HICDEP) a standardized format for data sharing. Standardized methods for data cleaning, imputation, and analyses will be employed.